Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

S. Kuninaka, S. I. Iida, T. Hara, M. Nomura, H. Naoe, T. Morisaki, M. Nitta, Yoshimi Arima, T. Mimori, S. Yonehara, Hideyuki Saya

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The serine protease Omi/HtrA2 was initially regarded as a proapoptotic molecule that proteolyses several proteins to induce cell death. Recent studies, however, indicate that loss of Omi protease activity increases susceptibility to stress-induced cell death. These complicated findings suggest that the protease activity of Omi is involved not only in apoptosis but also in cellular homeostasis. However, the targets which Omi uses to mediate this novel process are unknown. Previously, we showed that WARTS (WTS)/large tumor-suppressor 1 mitotic kinase interacts with the protein/discs-large protein/zonula (PDZ) domain of Omi and promotes its protease activity. We now report that WTS is a substrate for Omi protease activity, thus it is not only a regulator but also a downstream target of this protease. Interaction with Omi PDZ domain is required for WTS to be proteolysed. When caspase-9-deficient mouse embryonic fibroblasts (MEFs) were treated with staurosporine, WTS was proteolysed by activated endogenous Omi without induction of cell death. Therefore, protease activity of Omi and proteolysis of WTS are not necessarily required for cell death. We found that depletion of Omi from HeLa cells results in accelerated cell proliferation despite no significant change in the duration of mitosis. The depletion of WTS showed the same effect on S phase progression. Therefore, WTS proteolytic fragment(s) generated by Omi may act as an inhibitor of G1/S progression. Our data reveal a role for Omi-mediated processing of WTS in negative regulation of cell cycle progression at interphase, suggesting a novel function of Omi other than apoptosis.

Original languageEnglish
Pages (from-to)2395-2406
Number of pages12
JournalOncogene
Volume26
Issue number17
DOIs
Publication statusPublished - 2007 Apr 12
Externally publishedYes

Fingerprint

Peptide Hydrolases
Phosphotransferases
Cell Proliferation
Cell Death
Proteolysis
Apoptosis
Proteins
Staurosporine
Interphase
S Phase
HeLa Cells
Mitosis
Omi serine protease
Cell Cycle
Homeostasis
Fibroblasts
Neoplasms
Protein Domains

Keywords

  • Apoptosis
  • Cell cycle
  • Mitotic kinase
  • PDZ domain
  • Serine protease
  • Staurosporine

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Kuninaka, S., Iida, S. I., Hara, T., Nomura, M., Naoe, H., Morisaki, T., ... Saya, H. (2007). Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation. Oncogene, 26(17), 2395-2406. https://doi.org/10.1038/sj.onc.1210042

Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation. / Kuninaka, S.; Iida, S. I.; Hara, T.; Nomura, M.; Naoe, H.; Morisaki, T.; Nitta, M.; Arima, Yoshimi; Mimori, T.; Yonehara, S.; Saya, Hideyuki.

In: Oncogene, Vol. 26, No. 17, 12.04.2007, p. 2395-2406.

Research output: Contribution to journalArticle

Kuninaka, S, Iida, SI, Hara, T, Nomura, M, Naoe, H, Morisaki, T, Nitta, M, Arima, Y, Mimori, T, Yonehara, S & Saya, H 2007, 'Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation', Oncogene, vol. 26, no. 17, pp. 2395-2406. https://doi.org/10.1038/sj.onc.1210042
Kuninaka S, Iida SI, Hara T, Nomura M, Naoe H, Morisaki T et al. Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation. Oncogene. 2007 Apr 12;26(17):2395-2406. https://doi.org/10.1038/sj.onc.1210042
Kuninaka, S. ; Iida, S. I. ; Hara, T. ; Nomura, M. ; Naoe, H. ; Morisaki, T. ; Nitta, M. ; Arima, Yoshimi ; Mimori, T. ; Yonehara, S. ; Saya, Hideyuki. / Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation. In: Oncogene. 2007 ; Vol. 26, No. 17. pp. 2395-2406.
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